Neurons in human degenerative disease, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), develop a conspicuous neurofibrillary pathology in selected neruonal populations. My long-term objective is to understand some of the functional abnormalities occurring in these diseases, specifically the role of changes in axonal transport and neurotransmitters. My immediate goals in this proposal are to investigate the role of axonal transport in the production of cytoskeletal pathology in aluminum chloride (AlCl3) intoxication and to examine the consequences of this type of pathology on neurotransmitter-related properties of nerve cells. I also plan to study three additional animal models with documented changes in the cytoskeleton and in the axonal transport of motor neurons. First, in an extension of my previous investigations, I plan to examine the effects of AlCl3 intoxication on motor neurons, particularly on the axonal transport of slow components a (SCa) and b (SCb) in the sciatic nerve of the rabbit. Second, because the major biological property of neurons is neurotransmission mediated by neurotransmitters, synthesizing enzymes, and receptors, I plan to study cholinergic enzymes and a variety of receptors in the spinal cords of four animal models which are characterized by rearrangement or disorder of cytoskeletal elements. I plan to analyze changes in receptor populations (acetylcholine [ACh], glycine, gamma-aminobutyric acid [GABA], and benzodiazepine) and cholinergic enzymes (choline acetyltransferase [CAT] and acetylcholinesterase [AChE]) in aluminum myelopathy and in three models with documented changes in axonal transport (intoxication with Beta,Beta'-iminodipropionitrile [IDPN], Hereditary Canine Spinal Muscular Atrophy [HCSMA], and regeneration following sciatic nerve axotomy). The results of analysis of axonal transport, transmitter-specific activities, and receptors will be correlated with morphological observations at the light and electron microscopic level. I believe that, by using a variety of neurochemical and anatomical methods, I will gain new insights into the relationship between the appearance of cytoskeletal pathology and the development of dysfunction of motor neurons. This information should prove significant for our understanding of human degenerative disorders like ALS and AD.